This invention relates generally to valves used to control flow of liquid or gaseous materials and specifically to valves used in peptide synthesis.
Within this discussion, the use of the invention in relation to solid phase peptide synthesis will be used as an example. Those of ordinary skill in the art readily recognize various other applications where such valving proves commercially advantageous including, but not limited to, DNA synthesis and protein sequencing.
The solid phase method of peptide synthesis was first introduced by Professor R. B. Merrifield in 1964. This method drastically reduced the time required to chemically synthesize peptides by substantially simplifying the isolation and purification steps required in a chemical synthesis. This simplification was accomplished by attaching the carboxyl end of the C-terminal amino acid to an insoluble resin support (usually cross-linked polystyrene). All the chemical isolation and purification steps were then conducted on this insolubilized system. The method has been applied to the synthesis of a very large number of peptides on both a laboratory and commercial scale.
Professor Merrifield received a Nobel Prize in Chemistry for his contributions to science in 1985. Hundreds of scientific papers have been published describing variations on Merrifield's basic chemical approach. Several instruments have been designed and built by both academic and commercial laboratories to automate the solid phase method. The method has also been applied to the synthesis of deoxyribonucleic (DNA), ribonucleic (RNA), and polysaccarides.
In a typical solid phase synthesis of a peptide, there is a covalent attachment between the carboxyl end of an alpha protected amino acid and an insoluble resin support that is typically 1 to 2 percent divinylbenzene cross linked polystyrene with bead size of 200-400 mesh.
The next amino acid in the peptide chain is added by a series of chemical reactions that start with deprotection of the alpha amino group, washes for purification, and the coupling of a new protected amino acid followed by further washing for purification.
This process is repeated for each amino acid in the peptide chain. Chemical reactions and washing steps can be automated and a number of commercial instruments are now available for carrying out this task.
Once the peptide chain is constructed, it must be removed from the polymer support, the side chain protecting groups removed, isolated and purified.
For a good review of the state of art in peptide synthesis, see U.S. Pat. No. 4,668,476, entitled "Automated Peptide Synthesis Apparatus" issued to Bridgham et al. on May 26, 1987, incorporated hereinto by reference.
Automated production of peptide synthesis has taken two basic approaches: (i) the use of robotic arms to move and physically deposit the selected amino acid or reagent into the reaction vessel; or (ii) selectively channeling a flow of amino acid or reagent into the reaction vessel.
Robotic arms have provided a great deal of automation to be process. An articulated arm, once programmed to create the particular peptide, selects the appropriate vial of material and deposits that material into the reaction vessel. Through a sequence of deposits and waits, the desired peptide is produced.
Although the robotic method offers some distinct advantages, the mechanical movement of the amino acids is susceptible to spills. Another disadvantage is the time required to physically move the container and then replace it. Yet another disadvantage is the fact that robotic mechanisms are almost by definition single process type; that is, only one synthesis is possible at any one time.
Other disadvantages of the robotic system is that it is an "open system" which creates hazards to workers and is susceptible to contamination from the air. Still further, the robotic systems are limited in volume and are sequential in nature (one process at a time).
Because of these constraints on the robotics approach, most applications do not use the articulated arm for the synthesis of peptides.
The vast majority of applications utilize a valving operation to deliver the amino acid and reagent materials to the reaction chamber. In these devices, a supply of selected amino acids and reagent material are positioned to supply, via valves, the reaction vessel. In this manner, through selective activation or individual valves, the amino acid or reagent is communicated to the reaction vessel to build the peptide.
The use of valves eliminates the need to physically move containers and as such operates much faster and without the possibility of spills encountered with the robotic approach.
To this end, a larger number of patents have been obtained which relate to the valves themselves and their control. Examples of these patents include: U.S. Pat. No. 4,597,412, entitled "Valve for Sequential Chemical Operations" issued to Stark on Jul. 1, 1986; U.S. Pat. No. 4,595,565, entitled "Equipment for Mixing Liquid Reactants" issued to Tenhagen on Jun. 17, 1986; U.S. Pat. No. 4,281,683, entitled "Modular Multiple-Fluid Component Selection and Delivery System" issued to Hetherington et al. on Aug. 4, 1981; U.S. Pat. No. 3,784,169, entitled "Method of and Apparatus for the Controlled Mixing of Two Reactive Components" issued to Bockmann et al. on Jan. 8, 1974; and, U.S. Pat. No. 4,848,387, entitled "Method and Apparatus for Segregated Introduction of Two Liquids into a Chemical Reactor Vessel at a Common Entry Point" issued to Hon on Jul. 18, 1989, U.S. Pat. No. 4,008,736, entitled "Valve Arrangement for Distributing Fluids" issued to Wittman-Liebold et al. on Feb. 22, 1977.
Additionally, many different companies have tried their own unique designs for creating a grouping of valves. One such example is the valve used by Protein Technologies Inc. for its PS3 Peptide Synthesizer.
In all of these cases, the valve arrangements are of such complexity that only a single group of valves is possible, all of which address a single reaction vessel. This restriction is forced upon them by their own complex piping requirements.
Furthermore, these devices have some intrinsic drawbacks both in operating time and quality control. Once a particular liquid has passed through a valve and into the conduit to the reaction vessel, a residue is left behind. If not cleaned thoroughly, this residue from the previous liquid will affect later liquids and thus have a negative effect upon the quality of the peptide produced. Because of this concern, the physical structure of the valve and "pipes", conduits, or channels connecting everything is of pronounce importance. If improperly done, dead volumes are created which shield the residue from cleaning.
As the industry has expanded, the need for faster, more accurate, and of higher quality synthesis has increased. These above devices have not met this demand.